Saponins are a type of glycoside found in nature. A saponin is composed of a sapogenin and a sugar. The sugar can be a monosaccharide or an oligosaccharide. The sapogenin is asteroid or a triterpene.
The saponins found in soybeans, alfalfa, and ginseng have been studied extensively for their effect of lowering cholesterol. Both the animal's ability to absorb cholesterol as well as its level of serum cholesterol are reduced. The work on soybean saponins and lipid metabolism was performed by Ohominami, et al at the School of Medicine, Ehime University of Japan in 1981. This work is abstracted in CA96; 210724X. The work on ginseng is disclosed in CA101; 204131G. This work was done by Moon et al, University of Seoul, Korea. The effect of dietary alfalfa sprouts and alfalfa saponins is the subject of a dissertation by David L. Stone, University of California, Berkeley (CA 102; 165757Q). A mechanism for hypocholesterolemic activity of saponins was published by Sidhu et al in the British Journal of Nutrition in 1986.
Japanese Patent 86/249,364 assigned Osaka Yakuhin Kenky describes the use of a soyasaponin for preventing thrombosis. U.S. Pat. No. 4,242,502 issued to Malinow et al (assigned United States, 1980) relates to the use of saponins to inhibit cholesterol absorption. According to this reference, modification of the oligosaccharide portion of the saponin by hydrolysis under mild acid conditions affects the saponins' ability to affect cholesterol absorption.
U.S. Pat. No. 4,524,067 issued to Arichi et al (Osaka Chemical Laboratory, 1985) discloses the use of bean saponins for lowering cholesterol.
Ulloa et al, Biochim Biophys Acta, (1985), 837 (2) pp. 181-9 as abstracted in Index Medicus describes experiments in which different plant steroids, including saponins, increase biliary cholesterol secretion.
U.S. Pat. No. 4,602,003 issued to Malinow (1986) describes synthetic sapogenin and sterol compounds which inhibit the absorption of cholesterol and are used to treat hypercholesterolemia. These compounds are synthetic glycosides of tigogenin, diosgenin, smilagenin, and the like. Cellobiose-tigogenin and cellobiose-diosgenin were also made as were the ester derivatives.
U.S. Pat. No. 4,602,005 issued to Malinow (1986) is related to the 4,602,003 patent. Tigogenin cellobioside is described as being particularly effective for treating hypercholesterolemia and atherosclerosis.
The liver plays a central role in the regulation of blood cholesterol concentration and flux. It has long been recognized that manipulation of the enterohepatic circulation of cholesterol and/or bile acids is a means to change blood cholesterol levels, particularly low density lipoprotein cholesterol (LDL-C) levels, via influences on hepatic metabolism. Agents Which bind or otherwise prevent the absorption of cholesterol and bile acids across the gut wall, if given at a sufficient dose, will cause the liver to up-regulate the LDL receptor. The resultant drop in LDL concentrations is generally believed to provide significant therapeutic benefits.
While it is well known that saponins have a cholesterol lowering benefit, it is also well known that these materials hydrolyze in the digestive system. When the sugar moiety is removed, i.e., the glycosidic linkage is cleaved, the cholesterol is no longer removed. Therefore, a saponin derivative which does not hydrolyze in the stomach or intestine would be highly desirable. Such a compound could even be derived from cholesterol.
Surprisingly it has been found that derivatizing a sterol with a 5-C-hydroxymethyl substituted sugar provides a saponin derivative which is not hydrolyzed in the stomach or intestine, but still functions to lower cholesterol and serum triglycerides. The 5-C-hydroxymethyl sugars are the subject of U.S. Pat. No. 5,041,541 (1991).
It is an object of this invention to provide novel saponins which are poorly hydrolyzed in the digestive tract. It is a further object of this invention to provide novel compounds which lower the cholesterol absorbed by the body and also lower serum cholesterol levels in animal and human subjects. These and other objects will be evident from the discussion herein.
All percentages are by weight unless otherwise indicated.